Cell Discovery (Dec 2020)
A novel multistage antiplasmodial inhibitor targeting Plasmodium falciparum histone deacetylase 1
- Zhenghui Huang,
- Ruoxi Li,
- Tongke Tang,
- Dazheng Ling,
- Manjiong Wang,
- Dandan Xu,
- Maoxin Sun,
- Lulu Zheng,
- Feng Zhu,
- Hui Min,
- Rachasak Boonhok,
- Yan Ding,
- Yuhao Wen,
- Yicong Chen,
- Xiaokang Li,
- Yuxi Chen,
- Taiping Liu,
- Jiping Han,
- Jun Miao,
- Qiang Fang,
- Yaming Cao,
- Yun Tang,
- Jie Cui,
- Wenyue Xu,
- Liwang Cui,
- Jin Zhu,
- Gary Wong,
- Jian Li,
- Lubin Jiang
Affiliations
- Zhenghui Huang
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Ruoxi Li
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Tongke Tang
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Dazheng Ling
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Manjiong Wang
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Dandan Xu
- Department of Microbiology and Parasitology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity
- Maoxin Sun
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Lulu Zheng
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology
- Feng Zhu
- Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida
- Hui Min
- Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida
- Rachasak Boonhok
- Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida
- Yan Ding
- Department of Pathogenic Biology, Army Medical University
- Yuhao Wen
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Yicong Chen
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Xiaokang Li
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Yuxi Chen
- Department of Immunology, College of Basic Medical Sciences, China Medical University
- Taiping Liu
- Department of Pathogenic Biology, Army Medical University
- Jiping Han
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Jun Miao
- Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida
- Qiang Fang
- Department of Microbiology and Parasitology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity
- Yaming Cao
- Department of Immunology, College of Basic Medical Sciences, China Medical University
- Yun Tang
- Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology
- Jie Cui
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Wenyue Xu
- Department of Pathogenic Biology, Army Medical University
- Liwang Cui
- Division of Infectious Diseases and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida
- Jin Zhu
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Gary Wong
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- Jian Li
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology
- Lubin Jiang
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, University of Chinese Academy of Sciences, Chinese Academy of Sciences
- DOI
- https://doi.org/10.1038/s41421-020-00215-4
- Journal volume & issue
-
Vol. 6,
no. 1
pp. 1 – 15
Abstract
Abstract Although artemisinin combination therapies have succeeded in reducing the global burden of malaria, multidrug resistance of the deadliest malaria parasite, Plasmodium falciparum, is emerging worldwide. Innovative antimalarial drugs that kill all life-cycle stages of malaria parasites are urgently needed. Here, we report the discovery of the compound JX21108 with broad antiplasmodial activity against multiple life-cycle stages of malaria parasites. JX21108 was developed from chemical optimization of quisinostat, a histone deacetylase inhibitor. We identified P. falciparum histone deacetylase 1 (PfHDAC1), an epigenetic regulator essential for parasite growth and invasion, as a molecular target of JX21108. PfHDAC1 knockdown leads to the downregulation of essential parasite genes, which is highly consistent with the transcriptomic changes induced by JX21108 treatment. Collectively, our data support that PfHDAC1 is a potential drug target for overcoming multidrug resistance and that JX21108 treats malaria and blocks parasite transmission simultaneously.
